Chirality, or "handedness", is a term which was first applied by Lord Kelvin to any geometric shape having an image in a plane mirror which cannot be brought to coincide with itself, as with our left and right hands. Atoms to which different ligands are attached at each of three or four valances (e.g., carbon, nitrogen, phosphorus, etc.) form a chiral center, which is a necessary and sufficient condition for the existence of optically active mirror-image isomers known as enantiomers.
Enantiomers show different properties, both physical and chemical, only in a chiral medium, e.g. irradiation with plane or circularly polarized light, reaction with an optically active reagent, solubility in an optically active solvent, or adsorption onto an optically active surface.
The maximum number of stereoisomers that can exist is 2n where n is the number of chiral centers in a molecule Compounds containing a plurality of chiral centers can also exist as diastereomers, which are stereoisomers that are not mirror images of each other. Diastereomers have similar (but not identical) chemical properties and different physical properties which facilitate separation into their racemic mixtures which can then be resolved by the use of optically active reagents.
Characterization of a particular isomer's configuration is determined by applying a well-known set of sequence rules to assign priorities to the ligands which are attached to the chiral center, after which the molecule is visualized with the lowest priority ligand directed away from the viewer. If proceeding from the highest priority ligand to those of the second and third priority is a clockwise direction, the configuration is specified R; if counterclockwise, S. Because this configuration has no relationship to the direction of optical rotation, a complete name for an optically active compound reveals both configuration and direction of rotation, e.g. (S)-(+)-sec-butyl chloride.
Where compounds contain more than one chiral center, the configuration about each center is specified together with the nomenclature number of the chiral carbon atom, e.g. (2S,3S)- and (2R,3R)- compounds are enantiomers having opposite configurations for each chiral center, whereas (2S,3S)- and (2S,3R)- compounds would be diastereomers with the same configuration about one chiral center and the opposite configuration about the other.
Stereoisomers are ubiquitous building blocks in nature. For example, (+)-glucose contains five chiral centers which give rise to 32 stereoisomers. Naturally occurring glucose in the alpha-form is the monomeric unit of starch, from which our food ultimately comes, whereas beta-D-glucose is the monomeric unit of cellulose, the framework of plants that synthesize starch.
Glycerol is a simple trihydric alcohol having thousands of uses as an industrial chemical and as a starting material for the preparation of many pharmaceuticals by reactions which involve substitutions of one or more primary hydroxyl groups in the glycerol molecule. Such a substitution of glycerol (which has a "pro-chiral" center at C2 which is capable of becoming a chiral carbon atom) is a desired starting material for the synthesis of optically active glycerol derivatives. Because the synthesis of chiral compounds from achiral reactants always yields the optically inactive (RS) racemic mixture, the ability to generate a pure enantiomer starting material would effectively multiply the final yield of a desired isomer in products such as those prepared by a reaction that does not involve the breaking of a bond to a chiral center.
One example of a pharmaceutical glycerol derivative is the chiral synthon (chiron) 2,3-O-isopropylidene-L-glycerol or (R)-(-)-2,2-dimethyl-1,3- dioxolane-4-methanol described in K. H. X. Mai and G. Patil U.S. Pat. No. 4,575,558 as an important intermediate for preparing optically active beta-adrenergic agonists and antagonists and as a chiral building block in a number of natural products. The optically active glycerol derivatives used for the preparation of these molecules are derived from D- and L-serine. The presence of the substituted glycerol backbone in such compounds lends itself to synthesis using the methods of the present invention.
J. J. Baldwin and D. E. McClure U.S. Pat. No. 4,588,824 describe a process for preparing the (S)-enantiomer of Mai. et al., (S)-glycerol-1,2-acetonide or (S)-(+)-2,2-dimethyl-1,3-dioxolane-4-methanol by treating 1,2:5,6-di-O-isopropylidene-D-mannitol with lead tetraacetate in an aprotic solvent, reducing the optically active glyceraldehyde reaction product with an alkali metal borohydride and treating the reaction mixture with an ammonia halide to form the (S)-glycerol derivative. The product is a useful intermediate for the preparation of either the (S)- or (R)- enantiomer of epihalohydrins from the same starting material without requiring costly and inefficient racemic resolution procedures.
R. M. Carman and J. J. Kibby describe the preparation of chiral benzylidene derivatives of glycerol in Aust. J. Chem 29: 1761-67 (1976) by a method admittedly cumbersome, tedious, and difficult to duplicate.
J. Jarczak et al. have recently reviewed the role of (R)- and (S)-2,3-O-isopropylideneglyceraldehyde in stereoselective organic synthesis in Tetrahedron Report No. 195, Tetrahedron 142 (2): 447-487 (1986). Starting from the three-carbon glycerol backbone, techniques are described for building to compounds having 20 and more carbon atoms, e.g. lecithins, glycerol-3-phosphates, macrobicyclic polyethers and riboses (page 455); natural products including brefeldin (a sex pheromone), leukotrienes such as LTA4, and prostaglandins (see pages 479-485). The glyceraldehydes undergo many of the same chemical reactions as their corresponding glycerols but are less storage stable due to their tendency to polymerize.
Although the chemistry of L-ascorbic acid has been thoroughly studied, that of its C-5 isomer, D-isoascorbic acid, remains relatively unexplored. The synthetic utility of D-isoascorbic acid is not limited to the preparation of R- and S-glycerol derivatives. It, along with L-ascorbic acid, serves as an attractive precursor for the preparation of new selectively protected chiral erythritols and threitols, which, in their own right, are attractive building blocks in organic synthesis.
Synthetic approaches to 2-deoxy-2-amino-D-threose have been described in a 1982 thesis by David C. J. Wu (Department of Medicinal Chemistry, University of Rhode Island) as a potential synthon for adenosine deaminase inhibitors. However, there is no suggestion that the 3,4-O-isopropylidine-D-erythritol intermediate in that process would be useful as a source of enantiomerically pure R- or S- diasterreomers in accordance with the present invention.